Risk of non-alcoholic fatty liver disease in patients with psoriasis: a systematic review and meta-analysis.

BACKGROUND: Psoriasis has been linked to an increased risk of metabolic syndrome (MetS). Non-alcoholic fatty liver disease (NAFLD), the hepatic manifestation of MetS, is now the commonest liver disease worldwide and can evolve into cirrhosis in a subgroup of patients. Psoriasis has been reported to be associated to NAFLD. AIM: The aim of this study was to evaluate the strength of the association between psoriasis and NAFLD. METHODS: A systematic review of the literature was conducted in six databases (Medline, CINAHL, Scopus, LILACS, Cochrane Library and EMBASE). Data from studies assessing frequency of NAFLD in psoriatic and non-psoriatic patients were extracted and meta-analysed using the Mantel-Haenszel method. Subgroups analysis of patients with psoriatic arthritis and moderate to severe psoriasis was also performed. RESULTS: Seven case-control studies were included, all of them of low or moderate quality. Psoriatic patients exhibited an increased risk of NAFLD compared to non-psoriatic controls (six studies; n = 267,761 patients; odds ratio (OR): 2.15, 95% CI: 1.57-2.94). The association remained significant (OR: 2.07, 95% CI: 1.62-2.64) when only high/moderate quality studies were analysed (three studies; n = 3345 patients). The risk of NAFLD was significantly greater in patients with psoriatic arthritis (three studies; n = 505 patients; OR: 2.25, 95% IC: 1.37-3.71) and in patients with moderate to severe psoriasis compared to those with mild psoriasis (two studies; 51,930 patients, OR: 2.07, 95% CI: 1.59-2.71). LIMITATIONS: Data quality and heterogeneity may restrict the interpretation of the pooled risk estimates. CONCLUSION: Case-control studies support an association between psoriasis and NAFLD. Screening of NAFLD in this group of patients may be warranted.

Role of the femoral vein doppler in acute heart failure patients: results from a prospective multicentric study.

BACKGROUND AND OBJECTIVE: The aim of our study is to define the role of Pulsed-Doppler (PW-Doppler) Ultrasound of the Common Femoral Vein (CFV) in the assessment of dilatation Inferior Vena Cava (IVC), probability of Pulmonary Hypertension (PH), Tricuspid Regurgitation (TR), and Tricuspid annular plane systolic excursion (TAPSE). METHODS: This is a prospective two-hospital study in 74 patients admitted with acute heart failure (AHF). We performed PW-Doppler ultrasound of the common femoral vein, Point of Care (POC) cardiac ultrasonography and assessment of the IVC at the time of admission, as well as PW-Doppler and ultrasound of the IVC at hospital discharge. RESULTS: The detection of a pulsatile flow (138 scans) had an excellent ROC curve for the detection of IVC greater than 2cm (AUC 0.931, Sn 95%, Sp 90%, PPV 93%, NPV 94%) with an Odds Ratio (OR) of 211.2 (95% confidence interval 48.13-926.72). The pulsatility of the flow also had the highest performance in the detection of PH (AUC 0.8, Sn 95%, Sp 64%, PPV 84%, NPV 84%) and in the detection of moderate-severe TR (AUC 0.79, Sn 95%, Sp 67%, PPV 88%, NPV 78%). If the flow is continuous, we can reasonably rule out diminished TAPSE (NPV 89%). CONCLUSSION: Detection of PW-Doppler flow of the CFV may be an alternative window for the detection of an IVC dilation of 2cm, significant TR, and the likelihood of high PH in acute heart failure. It also allows us to reasonably rule out dysfunction of the right ventricle in cases of normality in these patients.

[Relationship between the alveolar-arterial oxygen gradient and PaO2/FiO2-introducing PEEP into the model]. / Relación entre el gradiente alveolo-arterial de oxígeno y la PaO2/FiO2 introduciendo la PEEP en el modelo.

OBJECTIVES: To determine whether the alveolar-arterial oxygen gradient (Grad[A-a]O2) helps confirm the influence of PEEP on PaFi (PaO2/FiO2). DESIGN: Observational study; we used linear regression to perform a multivariate study to improve the PaFi formula by taking PEEP into account. SETTING: Tertiary hospital. PATIENTS: We included all patients who were admitted to the intensive care unit, regardless of pulmonary damage. VARIABLES: We recorded personal history, clinical judgment, intensive care data, severity scores on the first day and progression. Two calculated variables: PaFi and Grad(A-a)O2. RESULTS: A total of 956 patients were included: 63.9% men; median age 68 years. On the first day, 31.8% did not have mechanical ventilation (MV), 13.1% had non-invasive MV and 55.1% had invasive MV. PaFi values: 32.9% 0-200, 32.2% 201-300, and 34.8% >300. PEEP values: 0-5 69.8%, 6-10 27.5% and >10 2.6%. We observed a correlation (Pearson) between Grad(A-a)O2 and PaFi of -0.84 (p<0.001). On performing multiple regression (dependent variable: Grad[A-a]O2), the following variables were included in the model: PaFi, PEEP, APACHE IV and SOFA; coefficient of determination (R²) of 0.62 without PEEP and 0.72 with PEEP. We changed the PaFi formula, referring to it as PaFip (PaFi plus PEEP): Ln (PaFi/[PEEP+12]). Correlation index between PaFip and Grad(A-a)O2: -0.9 (p<0.001). We performed linear regression (dependent variable: Grad[A-a]O2) and used PaFip instead of PaFi. Only PaFi remained in the model, and was discretely complemented by APACHE IV; R²=0.8. CONCLUSIONS: By adding PEEP to the PaFi model (PaFip), we clearly improve the latter, as reflected by a better goodness of fit.

Aramchol in patients with nonalcoholic steatohepatitis: a randomized, double-blind, placebo-controlled phase 2b trial.

Nonalcoholic steatohepatitis (NASH), a chronic liver disease without an approved therapy, is associated with lipotoxicity and insulin resistance and is a major cause of cirrhosis and hepatocellular carcinoma. Aramchol, a partial inhibitor of hepatic stearoyl-CoA desaturase (SCD1) improved steatohepatitis and fibrosis in rodents and reduced steatosis in an early clinical trial. ARREST, a 52-week, double-blind, placebo-controlled, phase 2b trial randomized 247 patients with NASH (n = 101, n = 98 and n = 48 in the Aramchol 400 mg, 600 mg and placebo arms, respectively; NCT02279524 ). The primary end point was a decrease in hepatic triglycerides by magnetic resonance spectroscopy at 52 weeks with a dose of 600 mg of Aramchol. Key secondary end points included liver histology and alanine aminotransferase (ALT). Aramchol 600 mg produced a placebo-corrected decrease in liver triglycerides without meeting the prespecified significance (-3.1, 95% confidence interval (CI) -6.4 to 0.2, P = 0.066), precluding further formal statistical analysis. NASH resolution without worsening fibrosis was achieved in 16.7% (13 out of 78) of Aramchol 600 mg versus 5% (2 out of 40) of the placebo arm (odds ratio (OR) = 4.74, 95% CI = 0.99 to 22.7) and fibrosis improvement by ≥1 stage without worsening NASH in 29.5% versus 17.5% (OR = 1.88, 95% CI = 0.7 to 5.0), respectively. The placebo-corrected decrease in ALT for 600 mg was -29.1 IU l-1 (95% CI = -41.6 to -16.5). Early termination due to adverse events (AEs) was <5%, and Aramchol 600 and 400 mg were safe, well tolerated and without imbalance in serious or severe AEs between arms. Although the primary end point of a reduction in liver fat did not meet the prespecified significance level with Aramchol 600 mg, the observed safety and changes in liver histology and enzymes provide a rationale for SCD1 modulation as a promising therapy for NASH and fibrosis and are being evaluated in an ongoing phase 3 program.

Pneumonyssoides species infestation in two Pekingese dogs in the UK.

Two male, neutered, Pekingese dogs aged four years and 12 years were presented for acute-onset nasal pruritus and sneezing following a visit to a beach in northern Scotland. Routine nasal investigations revealed the presence of the canine nasal mite Pneumonyssoides both by direct visualisation and histopathologically. Resolution of clinical signs was observed following selamectin treatment. To the authors' knowledge, this report describes the first cases of Pneumonyssoides infestation in non-travelled UK dogs.

Endotoxin downregulates rat hepatic ntcp gene expression via decreased activity of critical transcription factors.

Sodium-dependent uptake of bile acids across the hepatic basolateral membrane is rapidly and profoundly diminished during sepsis, thus contributing to the pathogenesis of sepsis-associated cholestasis. This effect is mediated by endotoxin or effector cytokines, which reduce expression of several hepatobiliary transporters, including the sodium-dependent bile acid transporter gene, ntcp. We test here the hypothesis that endotoxin treatment leads to impaired binding activity of ntcp promoter trans-acting factors, resulting in reduction of ntcp mRNA expression. After endotoxin administration, ntcp mRNA levels reached their nadir by 16 h, and nuclear run-on assays demonstrated a marked reduction in ntcp gene transcription. At 16 h after treatment, nuclear binding activities of two key factors that transactivate the ntcp promoter, hepatocyte nuclear factor (HNF) 1 and Footprint B binding protein (FpB BP), decreased to 44 and 47% of pretreatment levels, respectively, while levels of the other known ntcp promoter transactivator, signal transducer and activator of transcription 5, were unaffected. In contrast, the universal inflammatory response factors nuclear factor kappaB and activating protein 1 were both upregulated significantly. Examination of nuclear extracts obtained at sequential time points revealed that the maximal decrease in nuclear activities of both HNF1 and FpB BP preceded the nadir of ntcp mRNA expression by 6-10 h. Furthermore, these two nuclear factors returned towards normal levels before the recovery of ntcp mRNA levels observed by 48 h. Since HNF1alpha mRNA levels were unchanged at all time points, HNF1 is likely to be regulated posttranscriptionally by endotoxin. We conclude that the downregulation of ntcp gene expression by endotoxin is mediated at the level of transcription through tandem reductions in the nuclear binding activity of two critical transcription factors. These findings provide new insight into the coordinated downregulation of hepatobiliary transporters during sepsis.

Sublingual tacrolimus administration provides similar drug exposure to per-oral route employing lower doses in liver transplantation: a pilot study.

BACKGROUND: Per-oral tacrolimus administration is not always practicable. Sublingual administration is a potential alternative, but its feasibility and effectiveness compared with oral route has not been established. AIM: To compare tacrolimus drug exposure after sublingual and oral administration in liver transplant recipients. METHODS: Experimental, open-label, non-randomised, cross-over study. Tacrolimus exposure was evaluated in 32 liver transplant recipients receiving oral administration. 12 h tacrolimus area-under-the-curve (AUC0-12 h ) was calculated using tacrolimus blood concentrations at 0-0.5-1-2-4-6-8-12 hrs post-dose. Recipients were switched to sublingual administration, and dose was adjusted to reach similar trough levels, new AUC0-12 h was calculated. Correlation between AUC0-12 h and trough levels was determined for both oral and sublingual phases. RESULTS: Similar trough levels were accomplished with oral and sublingual administration (6.68 ± 2 ng/mL vs. 6.62 ± 1.9 ng/mL (P = 0.8)). Although concentration 2 h post dose was higher in oral phase (15.36 ± 7.14 vs. 13.18 ± 5.64, P = 0.015), AUC0-12 h was similar in both phases (116.6 ± 34.6 vs. 111.5 ± 36.93 ng/mL* h, P = 0.19). Daily dose of tacrolimus required in sublingual phase was 37% lower than that used in oral phase (P < 0.0001), suggesting significantly increased bioavailability of tacrolimus when employing sublingual route. Good correlation between AUC0-12 h and trough levels was observed in sublingual phase (r2 = 0.74). Twenty-two recipients were maintained on sublingual administration after the end of study (mean follow-up: 18.7 ± 5.8 months). No difference in liver function tests or rejection rates was found during follow-up period. CONCLUSIONS: Sublingual administration of tacrolimus is feasible and provides similar drug exposure compared with oral administration. In our study, at long-term follow-up, sublingual administration was not associated with liver transplant rejection.

Enhanced biliary excretion of canalicular membrane enzymes in ethynylestradiol-induced cholestasis. Effects of ursodeoxycholic acid administration.

Cholestasis is associated with a marked increase in the release of canalicular membrane enzymes into bile. This phenomenon has been related to an increased lability of these canalicular membrane integral proteins to the solubilizing effects of secreted bile salts. To further characterize the effects of oral ursodeoxycholic acid (UDCA) administration on ethynylestradiol (EE)-induced cholestasis, the influence of this bile acid on changes in biliary excretion of membrane-bound enzymes was investigated. Bile flow, basal bile salt and biliary lipid secretory rates, the maximum secretory rate of taurocholate (TC SRm), and the biliary excretion of the canalicular membrane-bound ectoenzymes alkaline phosphatase (ALP) and gamma-glutamyl transpeptidase (GGT) were measured in rats after EE and/or UDCA administration. The activities of ALP, GGT and Na+,K(+)-ATPase in purified isolated canalicular and sinusoidal membrane fractions and the ultrastructure of hepatic acinus, including histochemical studies of ALP distribution, were also examined. EE significantly reduced bile flow, bile salt and biliary lipid secretory rates, and TC SRm, and caused dilatation and loss of microvilli at the canalicular pole of hepatocytes. Biliary excretion of ALP increased 2-fold, whereas biliary excretion of GGT was unchanged. The relationship between biliary excretion of ALP or GGT and bile salt secretion (units of enzyme activity secreted per nanomole of bile salt) was greater in EE-treated rats compared with controls (2.1- and 1.5-fold greater for ALP and GGT, respectively), indicating that in EE-induced cholestasis more enzyme was released into bile per nanomole of bile salt. Na+,K(+)-ATPase activity in sinusoidal membrane fraction was reduced significantly, whereas ALP activity increased in both membrane fractions in EE-treated rats. The histochemical distribution of ALP in the acinus showed a strong reaction in acinar zone 3 and at both the canalicular and sinusoidal membranes. Oral administration of UDCA prevented EE-induced bile secretory failure by normalizing bile flow, bile salt and biliary phospholipid secretory rates, and TC SRm. UDCA also prevented the EE-induced changes in the biliary excretion of enzymes. On the contrary, UDCA did not modify either the enzyme activity in isolated membrane fractions or the morphological or ALP histochemical changes associated with EE administration. These data indicate that in EE-induced cholestasis changes occur at the canalicular membrane, enabling this portion of the plasma membrane to be more susceptible to the solubilizing effect of bile salt, and that oral administration of UDCA prevents bile secretory failure and changes in the biliary excretion of ALP and GGT in EE-treated rats.

Regulation of porphyrin biosynthesis in yeast. Level of delta-aminolevulinic acid in porphyrin mutants of Saccharomyces cerevisiae.

Saccharomyces cerevisiae mutants bearing mutations at the cyc4 locus are partially deficient in cytochrome synthesis. Although the mutation is not in the structural gene for delta-aminolevulinic acid (Alv) synthase, the mutants are deficient in Alv synthesis in vivo as indicated by abnormally low intracellular Alv concentrations. The cyc4 mutation causes cells to grow very slowly in minimal glucose medium, but not in yeast extract-peptone-glucose medium. A simple nutritional defect caused by the cyc4 mutation is not involved because cytochrome deficiency is enhanced by growing cyc4 cells in yeast extract-peptone medium. A regulatory role for CYC4 is indicated. Evidence for negative feed-back control of Alv synthase by heme is provided by the observation of enhanced intracellular Alv accumulation in yeast mutants partially deficient in decarboxylation of uroporphyrinogen and coproporphyrinogen, respectively.

Nuclear receptors, inflammation, and liver disease: insights for cholestatic and fatty liver diseases.

Members of the nuclear receptor (NR) superfamily of ligand-activated transcription factors are players of substantial relevance in the regulation of hepatic gene expression. NRs direct normal physiology and metabolism, adaptations to liver disease, and responses to inflammation and toxins.They also contribute to the regenerative response. In this review, we summarize currently available experimental and clinical data, focusing on the role of NRs in cholestasis and nonalcoholic fatty liver disease (NAFLD). We also highlight the potential of NRs as targets for safe and effective therapeutic interventions.

Liver transplantation results for hepatocellular carcinoma in Chile.

UNLABELLED: Hepatocellular carcinoma (HCC) is the most common malignant tumor of the liver. Liver transplantation is the best treatment for HCC; it improves survival, cures cirrhosis, and abolishes local recurrence. We describe the outcomes of patients with HCC who underwent liver transplantation in two liver transplantation centers in Chile. METHODS: This study is a clinical series elaborated from the liver transplantation database of Pontificia Universidad Católica and Clínica Alemana between 1993 and 2009. The survival of patients was calculated using the Kaplan-Meier survival analysis. The significant alpha level was defined as <.05. RESULTS: From 250 liver transplantations performed in this period, 29 were due to HCC. At the end of the study, 25 patients (86%) were alive. The mean recurrence-free survival was 30 months (range 5 months to 8 years). The 5-year survival for patients transplanted for HCC was >80%; however, the 5-year overall survival of patients who exceeded the Milan criteria in the explants was 66%. There was no difference in overall survival between patients transplanted for HCC versus other diagnosis (P = .548). CONCLUSION: This series confirmed that liver transplantation is a good treatment for patients with HCC within the Milan criteria.

Bridge therapy in hepatocellular carcinoma before liver transplantation: the experience of two Chilean centers.

BACKGROUND: Orthotopic liver transplantation (OLT) is currently an established therapy for small, early-stage hepatocellular carcinoma (HCC) within the Milan criteria. Long waiting times due to the shortage of donor organs can result in tumor progression and drop-out from OLT candidacy. Therefore a wide variety of procedures are necessary before OLT. The aim of this retrospective study was to review our experience in relation to bridge therapy prior to OLT for HCC. METHODS: This was a retrospective database review of all of the patient who underwent transplantation in our institutions between January 1993 and June 2009. We analyzed patients with a diagnosis of HCC in the explant. RESULTS: Among 29 patients, including 12 who were diagnosed by the explant and 17 prior to transplantation, 88% underwent bridge therapy during a mean waiting time to OLT of 12 months. Among the 23 procedures, namely 1.5 procedures per patient, included most frequently chemoembolization (48%), alcohol ablation (30%), radiofrequency ablation (13%), and surgery (9%). Thirty-three percent of the explants contained lesions within the Milan criteria. In our series the 5-year survival rate for patients transplanted for HCC was 86%; in the bridge therapy group, it was 73%. CONCLUSIONS: The incidence of patients who underwent bridge therapy (52%) was similar to other reported experiences, but the fulfillment of Milan criteria in the explants was lower. Among the bridge therapy group, the survival was slightly lower, probably because this group displayed more advanced disease.

[Identification of molecular defects in liver diseases. Recent advances]. / Identificación de defectos moleculares en las enfermedades hepáticas. Ejemplos recientes.

Recent molecular studies have resulted in the identification of genetic alterations underlying several hereditary disorders of the liver. Cloning of disease genes are increasing our understanding of the basic defects in liver diseases. This review focuses on selected inherited liver diseases such as hyperbilirubinemic syndromes, hemochromatosis, Wilson disease and genetic cholestatic syndromes and illustrate the knowledge gained on these disorders from molecular studies. Potential implications of the identification of disease genes such as practical applications for diagnosis, information on prognosis and the possibility to design new therapies are discussed.

[Ursodeoxycholic acid in the treatment of cholestatic liver diseases]. / Acido ursodeoxicólico en el tratamiento de enfermedades hepáticas colestásicas.

Ursodeoxycholic acid (UDCA) is a hydrophilic biliary acid that has been used in the medical therapy of cholelithiasis. In the last decade, its use in the treatment of some liver diseases renewed the interest on its hepato-protective properties. Controlled trials have demonstrated that UDCA has symptomatic and laboratory beneficial effects in primary biliary cirrhosis and sclerosing cholangitis. However its effects on the long-term and patients survival have not been determined. Uncontrolled trials on the effects of UDCA on a series of cholestatic liver diseases (cystic fibrosis, chronic hepatitis, cholestasis of pregnancy, etc) have communicated promising results that require confirmation with methodologically rigorous studies. The research in this area has significantly stimulated the study of the mechanisms of cellular injury associated to cholestatic phenomena and its prevention or attenuation with UDCA. The present review analyzes the most outstanding aspects of UDCA mechanisms of action, pharmacology and clinical efficacy in the treatment of liver diseases.

Serine 3 is critical for phosphorylation at the N-terminal end of the nucleoprotein of influenza virus A/Victoria/3/75.

The influenza A virus nucleoprotein (NP) is a phosphoprotein that encapsidates the viral genomic RNA. To map the in vivo phosphorylation site(s) of this protein, 32P-labeled NP was purified from cell cultures infected with influenza virus A/Victoria/3/75 by immunoaffinity chromatography. The purified protein was then subjected to chemical digestion with formic acid, which cleaves proteins at Asp-Pro bonds, and the resulting products were analyzed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Two of the phosphorylated products obtained were identified as fragments corresponding to the N-terminal 88 amino acids and to the C-terminal 196 residues of the NP. To identify the phosphate acceptor site(s) at the N-terminal phosphorylated region of NP, each of the seven serines within this region was individually changed to alanine by site-directed mutagenesis. The mutant proteins were then transiently expressed in mammalian cells and analyzed for their phosphorylation state. It was observed that the S-to-A mutation at position 3 drastically reduced the amount of 32P label incorporated into NP, whereas the other substitutions did not have a discernible effect on the phosphorylation level of the protein. In addition, all serine-altered proteins were tested for their functionality in an artificial system in which expression of a synthetic chloramphenicol acetyl-transferase RNA molecule is driven by influenza virus proteins synthesized from cloned genes. The results obtained demonstrate that all mutant proteins were competent to cooperate with the subunits of the viral polymerase for expression of the synthetic virus-like chloramphenicol acetyltransferase RNA in vivo. These data are discussed regarding the possible roles of NP phosphorylation for the viral replicative cycle.

[Molecular medicine: present and future]. / Medicina molecular: presente y futuro.

The genetic background of individuals is recognized as an important clue in the analysis of classical hereditary and multifactorial acquired diseases. This new concept derives from the development and increasing use of molecular genetics in clinical medicine. The application of molecular biology techniques in biomedical investigation has encompassed the identification of the pathogenesis and etiology of diseases, prenatal diagnosis the production of new therapeutic agents, gene therapy and the development of pharmacogenetics. The impact on the fundamentals and practice of clinical medicine that will have the use of molecular biology is analyzed in this review.

[Molecular biology and medicine: basic concepts]. / Biología molecular y medicina: conceptos básicos.

Through the advancements of molecular genetics, physicians and researchers are in an extraordinary period of study concerning the molecular basis of medicine. Molecular biology is making a tremendous impact on both diagnosis and treatment of diseases through the clinical introduction of molecular methods. These techniques, restricted for many years to basic biological research, include the polymerase chain reaction, DNA and protein electrophoresis, cloning of genes into viral or bacterial vectors and methods to rapidly sequence DNA and identify mutations. In this article the authors attempt to provide basic concepts on these themes for the non-trained physicians in order to help them to understand recent developments and foresee their future implications.

Hepatobiliary transport: molecular mechanisms of development and cholestasis.

The secretion of bile requires the vectorial transport of organic and inorganic solutes from sinusoidal blood to the canalicular lumen. Hydrostatic forces cannot account for biliary secretion, because secretory pressures within bile ducts exceed that of blood within the sinusoidal space. Instead, the process of bile formation requires active transport across the basolateral membrane, transcellular movement through a variety of mechanisms, and then active transport into the canalicular space between hepatocytes. Separate hepatic and ductular transport mechanisms allow for rapid regulation of bile volume and composition required for changing physiologic needs. The array of transport proteins localized to both poles of the hepatocyte have been characterized physiologically and during development. Many have now been cloned and studied further in transgenic models. The recent identification and characterization of several genes that are mutated in inherited forms of cholestatic liver disease have provided new insight into the normal physiology of bile secretion, the pathophysiology of intrahepatic cholestasis, and an unexpected major role for a novel group of P-type ATPases in human biology and disease.